Dual-release hydrocortisone improves hepatic steatosis in patients with secondary adrenal insufficiency: a real-life study

Abstract

Background: Conventional glucocorticoid treatment has a significant impact on liver in patients with adrenal insufficiency. Dual-release hydrocortisone (DR-HC) provides physiological cortisol exposure, leading to an improvement in anthropometric and metabolic parameters. We aimed to evaluate the effects of 12-month DR-HC treatment on the hepatic steatosis index (HSI), a validated surrogate index of hepatic steatosis, in patients with secondary adrenal insufficiency (SAI). Methods: A total of 45 patients with hypopituitarism, 22 with hypogonadism, hypothyroidism, ACTH, and GH deficiencies, and 23 with hypogonadism, hypothyroidism, and ACTH deficiency, on replacement therapy for all the pituitary deficiencies, were switched from conventional hydrocortisone to DR-HC. At baseline and after 12 months, glucose and insulin levels, surrogate estimates of insulin sensitivity, and hepatic steatosis were evaluated through ultrasonography and HSI. Results: At diagnosis, ultrasonography documented steatosis in 31 patients (68.8%) while 33 (73.3%) showed high HSI. Hydrocortisone (HC) dose (β = 1.231, p = 0.010), insulin resistance index (HOMA-IR) (β = 1.431, p = 0.002), and insulin sensitivity index (ISI)-Matsuda (β = −1.389, p = 0.034) were predictors of HSI at baseline. After 12 months of DR-HC, a significant decrease in body mass index (BMI) ( p = 0.008), waist circumference (WC) ( p = 0.010), fasting insulin ( p = 0.041), HOMA-IR ( p = 0.047), HSI ( p < 0.001) and number of patients with HSI ⩾36 ( p = 0.003), and a significant increase in sodium ( p < 0.001) and ISI-Matsuda ( p = 0.031) were observed. HOMA-IR (β = 1.431, p = 0.002) and ISI-Matsuda (β = −9.489, p < 0.001) were identified as independent predictors of HSI at 12 months. Conclusions: In adults with SAI, DR-HC is associated with an improvement in HSI, regardless of the dose used, mainly related to an improvement in insulin sensitivity.

Cortisol Circadian Rhythm and Insulin Resistance in Muscle: Effect of Dosing and Timing of Hydrocortisone Exposure on Insulin Sensitivity in Synchronized Muscle Cells

“…This considerable morbidity and mortality may be partially attributable to the disruption of GC circadian rhythmicity induced by the conventional GC formula-tions [42][43][44][45]. Indeed, the most commonly used conventional IR-HC thrice daily treatment schedule is associated with a nonphysiological cortisol daily pattern, not providing an adequate GC physiological replacement therapy, mainly due to the high circulating cortisol levels in the evening [46][47][48][49][50][51][52][53][54]. Recently, the novel MR-HC formulation appeared able to improve metabolic, as well as cardiovascular, skeletal, immune, and probably infectious complications, with positive impact on quality of life when compared to conventional GC formulations [46][47][48][49][50][51][52][53][54].…”

“…The GC overexposure has been found to be associated with an increased mortality [40,41] and an increased risk of developing the typical CS comorbidities, including metabolic syndrome [42,43], characterized by insulin resistance and glucose intolerance or diabetes [44,45]. More recently, patients treated with conventional GC formulations, especially immediate-release hydrocortisone (IR-HC), administered twice or thrice daily, and therefore exposed to nonphysiological pattern of cortisol circadian profile, but to daytime cortisol peaks and troughs, and particularly to the elevated evening cortisol levels, have shown more deleterious effects, especially on metabolic state, when compared to patients treated with the novel formulation of modified-release hydrocortisone (MR-HC) [46][47][48][49][50][51][52][53][54]. Indeed, a novel MR-HC formulation, based on an immediate release coating, together with an extended release core, orally administered once daily in the morning, was found to better mimic the cortisol circadian profile by reducing diurnal cortisol peaks and troughs and particularly the evening cortisol overexposure, with notable improvement in metabolic state [46][47][48][49][50][51][52][53][54], suggesting that the achievement of the optimal GC timing, beyond dosing, is relevant for the maintenance of a better metabolic profile.…”

The use of prednisolone versus dual-release hydrocortisone in the treatment of hypoadrenalism

“…There is also evidence of other metabolic benefits including improvement of hepatic steatosis ( 45 ). In 45 patients with secondary adrenal insufficiency, 25 of whom were already being treated with hydrocortisone and 20 yet to start replacement, Plenadren was administered for a 12-month period.…”

“…In order to mitigate against this, the current summary of product characteristics (SmPC) for Plenadren encourages individualisation of replacement doses when patients switch from other treatments ( 51 ). As a result, there is a trend towards escalation of the total daily dose in patients who have switched to Plenadren from real-world evidence ( 44 , 45 ). By restoring the cortisol exposure to baseline with these dose increases, it is possible that the benefits to the surrogate endpoints seen in the randomised trials (which relied on 1:1 daily dose switching to Plenadren) may not be realised in routine clinical use.…”

Terapia sostitutiva corticosteroidea alla luce delle nuove proposte farmacologiche (Plenadren®)

“…Lo stesso gruppo [15] nel 2019 ha valutato gli effetti metabolici e cardiovascolari della terapia con DR-HC per 18 mesi in un gruppo di 53 pazienti, sia primari che secondari, confrontato con un gruppo di 47 pazienti in terapia convenzionale, mostrando una riduzione di BMI, giro vita, pressione arteriosa diastolica, LDL colesterolo, HbA1C e rischio cardiovascolare (Framinghan Risk Score, FRS) nel gruppo di pazienti in DR-HC rispetto al gruppo in HC. In un altro studio [16] condotto nello stesso periodo, gli stessi autori hanno osservato come la terapia con DR-HC riduce il grado di steatosi (Hepatic Steatosis Index, HSI) in un gruppo di 45 pazienti con forma secondaria, di cui 20 casi naive per DR-HC, ol-Tabella 3 Studi clinici sul profilo di sicurezza del DR-HC. PAI, insufficienza surrenalica primaria; SAI, insufficienza surrenalica secondaria; CAH, sindrome adrenogenitale classica; PAS, pressione arteriosa si-stolica; PAD, pressione arteriosa diastolica; CA, cortone acetato; HC, idrocortisone; EAs, evento avverso Complessivamente, i risultati di questi studi mostrano che il trattamento con DR-HC migliori alcuni parametri antropometrici e metabolici rispetto al trattamento con HC, soprattutto in pazienti con insufficienza surrenalica primaria e vari gradi di insulino-resistenza, mentre i risultati nel paziente con insufficienza surrenalica secondaria, desunti da un campione meno numeroso, non risultano concordi nel dimostrare una superiorità del DR-HC all'HC (Tabella 2).…”